The increased glycolysis in cancer cells has been well accepted to be an important process to support malignant phenotypes. Previous reports have shown that lactate dehydrogenase A (LDH-A), an enzyme in the glycolytic pathway, and heat shock factor 1 (HSF1), a multifunctional transcription factor, play critical roles in cancer cell development and regulation of glucose metabolism. Overexpression of the oncogene ErbB2 increases the transformation and invasion/metastatic potentials of breast cancers. However, only recently has data emerged that directly links ErbB2 to increased glycolysis. The mechanism underling ErbB2-mediated glycolysis and the role of ErbB2-mediated glycolysis in cancer development remains poorly understood. Our preliminary data have demonstrated that: 1) overexpression of ErbB2 promotes glycolysis in human breast cancer cells, 2) overexpression of ErbB2 transcriptionally activates LDH-A and promotes glycolysis, 3) overexpression of ErbB2 upregulates HSF1 through a post-transcriptional control mechanism, 4) ErbB2 upregulates LDH-A through HSF1, and 5) Herceptin, an ErbB2-targeting antibody, effectively inhibits metabolism-regulating PI3K/Akt/mTOR signaling and HSF1 expression. Based on previous reports and our preliminary studies, we hypothesize that in human breast cancer cells ErbB2 upregulates LDH-A through HSF1. This pathway plays an important role in promoting ErbB2-mediated glycolysis and cancer development. Inhibition of glycolysis will at least partially reverse ErbB2-mediated malignant behavior, and the combination of Herceptin, which inhibits ErbB2, with a glycolysis inhibitor will better inhibit ErbB2-overexpressing breast cancer cells. We will test these hypotheses through the pursuit of the following specific aims: Aim 1: To study the role of HSF1 in ErbB2-enhanced glycolysis, cell transformation, and invasion. Aim 2: To study the mechanism of upregulation of HSF1 by ErbB2. Aim 3: To study the mechanism of upregulation of LDH-A by HSF1. Aim 4: To determine whether the combination of an ErbB2- targeting agent with glycolysis inhibitors will enhance inhibition of transformation and invasion/metastasis of ErbB2-overexpressing breast cancers. Successful completion of the proposed studies will provide a better understanding of the impact of ErbB2-increased glycolysis on breast cancer transformation and invasion/metastasis and will substantially augment our knowledge of the molecular mechanisms underlying ErbB2-mediated glycolysis. Furthermore, new insights into the unique ErbB2-mediated metabolism in breast cancer cells that result from these studies may lead to a more effective targeted cancer therapy for treating ErbB2-overexpressing cancers. PUBLIC HEALTH RELEVANCE: Oncogene ErbB2 may enhance glycolysis, a hallmark of cancer cells, to promote cancer development. The goal of this project is to determine the impact and mechanism of ErbB2 overexpression on altering the glucose metabolism of cancer cells, and to exploit the unique bioenergetics of cancer cells in order to develop novel strategies for selectively targeting cancer cells. New insights into the ErbB2-mediated metabolism in breast cancer cells that result from these studies may lead to a more effective targeted cancer therapy for treating ErbB2-overexpressing cancers.